GO:0014739 positive regulation of muscle hyperplasia: Vascular Smooth Muscle Proliferation, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0014739 (positive regulation of muscle hyperplasia) describes any process that activates or increases the frequency, rate or extent of muscle hyperplasia, the abnormal increase in muscle cell number.
• In the vasculature, this process is best studied in vascular smooth muscle cells (VSMCs), where neointimal hyperplasia after injury is driven by increased proliferation, migration and phenotypic switching [1,2,5,6,7,8].
• Key molecular drivers include Nrf3-Trim5 signaling, PCSK9, PRMT5-mediated KLF4 stabilization, ferroptosis induction, NR1D1, MTMR7-p62/mTORC1 glucose metabolism and SNHG18 [1,2,3,5,6,7,8].
• Dysregulated positive regulation of muscle hyperplasia underlies neointimal hyperplasia, atherosclerosis and restenosis, and is a therapeutic target in cardiovascular disease [1,2,3,5,6,7,8].
• CRISPR knockout, point mutation, knock-in and overexpression models enable causal testing of candidate genes in VSMC hyperplasia [1,2,3,5,6,7,8].
• EDITGENE provides end-to-end CRISPR cell model and library screening services to dissect positive regulation of muscle hyperplasia.
Description
GO:0014739, positive regulation of muscle hyperplasia, is a biological process term that captures any signaling or cellular event that increases the frequency, rate or extent of muscle hyperplasia, defined as an abnormal increase in muscle cell number [1,2,5,6,7,8]. Unlike muscle hypertrophy, which involves cell enlargement, hyperplasia reflects genuine proliferation of muscle cells, and its positive regulation is therefore central to conditions where muscle mass expands pathologically [1,2,5,6,7,8]. In the cardiovascular system, the most extensively characterized setting is injury-induced neointimal hyperplasia, where vascular smooth muscle cells (VSMCs) switch from a contractile to a synthetic, proliferative phenotype and accumulate in the intima [1,2,5,6,7,8]. This process is driven by a network of positive regulators, including Nrf3-Trim5, PCSK9, PRMT5-KLF4, ferroptosis-related pathways, NR1D1, MTMR7-p62/mTORC1 and SNHG18 [1,2,3,5,6,7,8]. Understanding these positive regulators is essential for developing therapies that limit pathological muscle hyperplasia without compromising normal vascular function [1,2,3,5,6,7,8].
positive regulation of muscle hyperplasia At A Glance
| GO ID | GO:0014739 |
|---|---|
| GO term | positive regulation of muscle hyperplasia |
| Ontology | biological_process |
| Synonym | none |
| Major function | Activates or increases the frequency, rate or extent of muscle hyperplasia |
| Related process | Muscle hyperplasia, vascular smooth muscle cell proliferation, neointimal hyperplasia |
| Disease relevance | Neointimal hyperplasia, atherosclerosis, restenosis, cardiovascular disease |
| Key regulators | Nrf3-Trim5, PCSK9, PRMT5-KLF4, ferroptosis, NR1D1, MTMR7-p62/mTORC1, SNHG18 |
What Is GO:0014739?
Positive regulation of muscle hyperplasia (GO:0014739) refers to any process that activates or increases the frequency, rate or extent of muscle hyperplasia, the abnormal increase in muscle cell number [1,2,5,6,7,8]. It is a biological process term that encompasses upstream signaling, transcriptional and post-transcriptional control, and metabolic reprogramming that collectively promote excessive muscle cell proliferation [1,2,3,5,6,7,8].
Why Is positive regulation of muscle hyperplasia Important in Cell Biology?
Positive regulation of muscle hyperplasia is critically important because excessive muscle cell proliferation underlies major human diseases, particularly vascular neointimal hyperplasia, atherosclerosis and restenosis after angioplasty or stenting [1,2,3,5,6,7,8]. Identifying the positive regulators of this process provides mechanistic insight and therapeutic targets, as demonstrated by studies showing that Nrf3-Trim5, PCSK9, PRMT5-KLF4, ferroptosis, NR1D1, MTMR7-p62/mTORC1 and SNHG18 modulate VSMC proliferation, migration and neointimal formation [1,2,3,5,6,7,8]. Understanding these pathways is essential for developing interventions that selectively inhibit pathological hyperplasia while preserving normal vascular homeostasis [1,2,3,5,6,7,8].
• Drives neointimal hyperplasia after vascular injury, a major cause of restenosis [1,2,3,5,6,7,8].
• Promotes VSMC phenotypic switching from contractile to synthetic, proliferative states [5,7,8].
• Involves metabolic reprogramming, including glucose metabolism via MTMR7-p62/mTORC1.
• Is modulated by epigenetic regulators such as PRMT5-mediated arginine methylation of KLF4.
• Is influenced by lipid-independent actions of PCSK9 on VSMC proliferation, migration and autophagy.
• Ferroptosis induction can aggravate neointimal hyperplasia via VSMC phenotypic switching.
• Nuclear receptor NR1D1 regulates VSMC proliferation and migration, affecting intimal hyperplasia.
• SNHG18 controls VSMC contractile phenotype and neointimal hyperplasia.
• Nrf3-Trim5 axis is a novel regulator of VSMC dysfunction and neointimal hyperplasia.
• Provides targets for CRISPR-based therapeutic intervention in cardiovascular disease [1,2,3,5,6,7,8].
What Happens During positive regulation of muscle hyperplasia?
Initiation by injury or stress signals
In simple terms: When blood vessels are injured, muscle cells receive signals to start multiplying.
Vascular injury triggers a cascade of positive regulatory signals that initiate muscle hyperplasia. Nrf3-Trim5 axis activation contributes to VSMC dysfunction and neointimal hyperplasia. PCSK9 promotes vascular neointimal hyperplasia through non-lipid regulation of VSMC proliferation, migration and autophagy. PRMT5-mediated arginine methylation stabilizes KLF4 to accelerate neointimal formation. These early events set the stage for excessive muscle cell proliferation [1,2,3].
Phenotypic switching and proliferation
In simple terms: Muscle cells change from a quiet, contractile state to a growing, synthetic state.
Positive regulation of muscle hyperplasia involves a phenotypic switch of VSMCs from contractile to synthetic, proliferative states. Ferroptosis induction promotes VSMC phenotypic switching and aggravates neointimal hyperplasia in mice. NR1D1 regulates VSMC proliferation and migration, influencing vascular intimal hyperplasia. MTMR7 suppresses phenotypic switching via p62/mTORC1-mediated glucose metabolism, and its loss enhances hyperplasia. SNHG18 controls VSMC contractile phenotype and neointimal hyperplasia. These studies demonstrate that multiple positive regulators converge on phenotypic switching and proliferation [5,6,7,8].
Metabolic and epigenetic reprogramming
In simple terms: Cells change their metabolism and gene-reading patterns to support rapid growth.
Metabolic and epigenetic reprogramming supports sustained muscle hyperplasia. MTMR7 regulates p62/mTORC1-mediated glucose metabolism, and its suppression promotes VSMC phenotypic switching and intimal hyperplasia. PRMT5-mediated arginine methylation stabilizes KLF4, accelerating neointimal formation. PCSK9 modulates autophagy in VSMCs, contributing to neointimal hyperplasia. These adaptations provide energy and transcriptional programs needed for hyperplasia [2,3,7].
Migration and neointimal formation
In simple terms: Multiplying muscle cells move into the vessel wall and form a thickened layer.
Positive regulation of muscle hyperplasia culminates in VSMC migration and neointimal formation. Nrf3-Trim5 axis promotes VSMC dysfunction and neointimal hyperplasia. PCSK9 enhances VSMC migration and neointimal hyperplasia. NR1D1 influences VSMC migration and vascular intimal hyperplasia. SNHG18 controls VSMC contractile phenotype and neointimal hyperplasia. These processes lead to intimal thickening and vascular stenosis [1,2,6,8].
Key Genes Involved in GO:0014739 positive regulation of muscle hyperplasia
The following genes and pathways have been experimentally implicated in positive regulation of muscle hyperplasia, primarily in vascular smooth muscle cell models and injury-induced neointimal hyperplasia [1,2,3,5,6,7,8].
| Gene | Major Role | Research Relevance |
|---|---|---|
| Nrf3 (NFE2L3) | Part of Nrf3-Trim5 axis regulating VSMC dysfunction | Novel regulator of neointimal hyperplasia |
| Trim5 | E3 ubiquitin ligase in Nrf3-Trim5 axis | Modulates VSMC dysfunction and neointimal hyperplasia |
| PCSK9 | Non-lipid regulation of VSMC proliferation, migration, autophagy | Promotes vascular neointimal hyperplasia |
| PRMT5 | Arginine methyltransferase stabilizing KLF4 | Accelerates neointimal formation |
| KLF4 | Transcription factor stabilized by PRMT5 | Promotes neointimal formation |
| MIF | Macrophage migration inhibitory factor, expressed in endometrial cancer | Potential marker in endometrial cancer |
| c-erbB-2 (ERBB2) | Receptor tyrosine kinase, expressed in endometrial cancer | Potential marker in endometrial cancer |
| Ferroptosis pathway | Iron-dependent cell death promoting VSMC phenotypic switching | Aggravates neointimal hyperplasia |
| NR1D1 | Nuclear receptor regulating VSMC proliferation and migration | Influences vascular intimal hyperplasia |
| MTMR7 | Phosphatase regulating p62/mTORC1 glucose metabolism | Suppresses VSMC phenotypic switching and intimal hyperplasia |
| p62 (SQSTM1) | Autophagy receptor in MTMR7-mTORC1 pathway | Mediates glucose metabolism in VSMC |
| mTORC1 | Kinase complex controlling metabolism and growth | Regulates VSMC phenotypic switching |
| SNHG18 | Small nucleolar RNA host gene 18 | Controls VSMC contractile phenotype and neointimal hyperplasia |
| KLF4-PRMT5 axis | Epigenetic stabilization of KLF4 | Drives neointimal formation |
| PCSK9-autophagy axis | Autophagy regulation in VSMC | Promotes neointimal hyperplasia |
| Nrf3-Trim5 axis | Ubiquitin-proteasome regulation | Modulates VSMC dysfunction |
| NR1D1 target genes | Circadian nuclear receptor targets | Regulate VSMC proliferation and migration |
How Is positive regulation of muscle hyperplasia Regulated?
Positive regulation of muscle hyperplasia is controlled by a multilayered network. Nrf3-Trim5 axis regulates VSMC dysfunction and neointimal hyperplasia. PCSK9 promotes VSMC proliferation, migration and autophagy via non-lipid mechanisms. PRMT5-mediated arginine methylation stabilizes KLF4 to accelerate neointimal formation. Ferroptosis induction promotes VSMC phenotypic switching and aggravates neointimal hyperplasia. NR1D1 modulates VSMC proliferation and migration. MTMR7 suppresses phenotypic switching via p62/mTORC1-mediated glucose metabolism. SNHG18 controls VSMC contractile phenotype and neointimal hyperplasia. These regulators form an integrated network that positively regulates muscle hyperplasia [1,2,3,5,6,7,8].
positive regulation of muscle hyperplasia and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| Nrf3-Trim5 | Neointimal hyperplasia | VSMC knockout and overexpression |
| PCSK9 | Neointimal hyperplasia, atherosclerosis | VSMC knockout and overexpression |
| PRMT5-KLF4 | Neointimal formation | VSMC knockout and point mutation |
| Ferroptosis pathway | Neointimal hyperplasia | VSMC knockout and ferroptosis induction |
| MTMR7-p62/mTORC1 | Intimal hyperplasia, glucose metabolism | VSMC knockout and knock-in |
Neointimal hyperplasia and restenosis
Positive regulation of muscle hyperplasia is directly linked to neointimal hyperplasia after vascular injury, a major cause of restenosis following angioplasty or stenting [1,2,3,5,6,7,8]. Nrf3-Trim5 axis, PCSK9, PRMT5-KLF4, ferroptosis, NR1D1, MTMR7-p62/mTORC1 and SNHG18 all modulate VSMC proliferation, migration and neointimal formation [1,2,3,5,6,7,8]. Targeting these positive regulators may reduce restenosis [1,2,3,5,6,7,8].
Atherosclerosis and cardiovascular disease
VSMC hyperplasia contributes to atherosclerotic plaque progression and vascular remodeling [1,2,3,5,6,7,8]. PCSK9, beyond lipid regulation, promotes VSMC proliferation and migration, linking positive regulation of muscle hyperplasia to atherosclerosis. NR1D1 and MTMR7 influence VSMC phenotype and intimal hyperplasia, relevant to cardiovascular disease [6,7]. SNHG18 and Nrf3-Trim5 axis further connect VSMC dysfunction to vascular pathology [1,8].
Cancer and other proliferative disorders
Although less directly studied, muscle hyperplasia shares proliferative mechanisms with cancer. MIF and c-erbB-2 expression has been examined in endometrial cancer, suggesting potential links between proliferative signaling and tumor biology. However, direct evidence for GO:0014739 in cancer remains limited, and most mechanistic data come from vascular models [1,2,3,5,6,7,8].
From positive regulation of muscle hyperplasia-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate gene reduce VSMC hyperplasia? | CRISPR knockout in VSMC lines or primary VSMCs [1,2,3,5,6,7,8] |
| Does a specific point mutation alter protein function in hyperplasia? | CRISPR point mutation knock-in in VSMCs [3,7] |
| Does tagging a protein reveal its localization during hyperplasia? | CRISPR knock-in of fluorescent or epitope tag [1,7] |
| Does overexpression of a candidate gene drive hyperplasia? | CRISPR overexpression or lentiviral overexpression in VSMCs [2,5,6,8] |
| Which genes are essential for VSMC proliferation? | CRISPR library screening in VSMCs [1,2,3,5,6,7,8] |
| Does a candidate gene affect neointimal formation in vivo? | Mouse vascular injury model with VSMC-specific manipulation [1,2,3,5,6,7,8] |
How to Study the positive regulation of muscle hyperplasia Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss-of-function effects | Test candidate gene necessity in VSMC hyperplasia [1,2,3,5,6,7,8] |
| CRISPR point mutation | Specific residue function | Dissect KLF4 stabilization by PRMT5 |
| CRISPR knock-in | Tagged protein localization | Track Nrf3-Trim5 or MTMR7 in VSMCs [1,7] |
| Overexpression | Gain-of-function effects | Test PCSK9, NR1D1 or SNHG18 sufficiency [2,6,8] |
| RNA-seq | Transcriptome changes | Identify downstream targets in VSMC hyperplasia [2,3,7,8] |
| Proteomics | Protein abundance and modifications | Study PRMT5-mediated methylation |
| Immunofluorescence | Protein localization and phenotype | Assess VSMC phenotypic switching [5,6] |
| Vascular injury model | Neointimal hyperplasia in vivo | Validate targets in mice [1,2,3,5,6,7,8] |
CRISPR knockout and point mutation
CRISPR knockout and point mutation are used to test causal roles of candidate genes in positive regulation of muscle hyperplasia. Knockout of Nrf3-Trim5, PCSK9, PRMT5, ferroptosis regulators, NR1D1, MTMR7 or SNHG18 in VSMCs can reveal effects on proliferation, migration and phenotypic switching [1,2,3,5,6,7,8]. Point mutations can dissect specific residues, such as those in KLF4 stabilized by PRMT5.
Transcriptomics and proteomics
RNA-seq and proteomics quantify global changes in gene expression and protein abundance during VSMC hyperplasia. Studies of PCSK9, PRMT5-KLF4, MTMR7-p62/mTORC1 and SNHG18 have used such approaches to identify downstream effectors [2,3,7,8]. These methods help define the molecular signature of positive regulation of muscle hyperplasia [2,3,7,8].
Imaging and phenotypic assays
Immunofluorescence, live-cell imaging and proliferation/migration assays measure VSMC phenotypic switching and hyperplasia. Ferroptosis induction and NR1D1 studies used these assays to link molecular changes to cellular behavior [5,6]. Such methods are essential for validating CRISPR phenotypes [5,6].
In vivo vascular injury models
Mouse vascular injury models, such as carotid artery ligation or balloon injury, assess neointimal hyperplasia in vivo. Nrf3-Trim5, PCSK9, PRMT5-KLF4, ferroptosis, NR1D1, MTMR7 and SNHG18 have been tested in such models [1,2,3,5,6,7,8]. These models provide physiological relevance to in vitro findings [1,2,3,5,6,7,8].
How CRISPR Can Be Used to Study GO:0014739 positive regulation of muscle hyperplasia
Knockout
CRISPR knockout of candidate genes such as Nrf3, Trim5, PCSK9, PRMT5, NR1D1, MTMR7 or SNHG18 in VSMCs can determine whether they are required for positive regulation of muscle hyperplasia [1,2,3,5,6,7,8]. Knockout studies have shown effects on proliferation, migration and neointimal formation [1,2,3,5,6,7,8].
Point Mutation
CRISPR point mutation introduces specific amino acid changes to dissect domain functions. For example, mutations in KLF4 can test its stabilization by PRMT5-mediated arginine methylation. Point mutations in MTMR7 can probe its phosphatase activity in glucose metabolism.
Knock-in
CRISPR knock-in of tags or reporters enables visualization and tracking of proteins such as Nrf3-Trim5 or MTMR7 during VSMC hyperplasia [1,7]. Knock-in of disease-associated variants can model human genetic contributions to neointimal hyperplasia [1,7].
Overexpression
CRISPR overexpression or lentiviral overexpression of PCSK9, NR1D1, SNHG18 or ferroptosis regulators can test sufficiency in driving VSMC hyperplasia [2,5,6,8]. Overexpression models complement knockout studies to establish causality [2,5,6,8].
How EDITGENE Supports positive regulation of muscle hyperplasia Research
Researchers studying positive regulation of muscle hyperplasia-related genes often need to determine whether a candidate gene is causally involved in VSMC proliferation, migration and neointimal formation. EDITGENE provides CRISPR-based cell model services to enable such causal testing with high efficiency and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of muscle hyperplasia research.
Frequently Asked Questions About positive regulation of muscle hyperplasia
What is GO:0014739 positive regulation of muscle hyperplasia?
GO:0014739 is a biological process term describing any process that activates or increases the frequency, rate or extent of muscle hyperplasia, the abnormal increase in muscle cell number [1,2,5,6,7,8].
What genes are involved in positive regulation of muscle hyperplasia?
Key genes include Nrf3, Trim5, PCSK9, PRMT5, KLF4, NR1D1, MTMR7, p62, mTORC1 and SNHG18, as well as ferroptosis-related pathways [1,2,3,5,6,7,8].
How is positive regulation of muscle hyperplasia studied?
It is studied using CRISPR knockout, point mutation, knock-in and overexpression in VSMCs, combined with RNA-seq, proteomics, imaging and in vivo vascular injury models [1,2,3,5,6,7,8].
What diseases are linked to positive regulation of muscle hyperplasia?
Neointimal hyperplasia, atherosclerosis, restenosis and cardiovascular disease are linked to excessive VSMC hyperplasia [1,2,3,5,6,7,8].
What is the role of PCSK9 in muscle hyperplasia?
PCSK9 promotes vascular neointimal hyperplasia through non-lipid regulation of VSMC proliferation, migration and autophagy.
How does PRMT5 regulate muscle hyperplasia?
PRMT5-mediated arginine methylation stabilizes KLF4, accelerating neointimal formation.
What is the role of MTMR7 in VSMC hyperplasia?
MTMR7 suppresses VSMC phenotypic switching and intimal hyperplasia via p62/mTORC1-mediated glucose metabolism.
How does SNHG18 affect neointimal hyperplasia?
SNHG18 controls VSMC contractile phenotype and neointimal hyperplasia.
Can CRISPR be used to study positive regulation of muscle hyperplasia?
Yes, CRISPR knockout, point mutation, knock-in and overexpression are widely used to dissect gene function in VSMC hyperplasia [1,2,3,5,6,7,8].
What models are suitable for studying positive regulation of muscle hyperplasia?
VSMC cell lines, primary VSMCs and mouse vascular injury models are commonly used [1,2,3,5,6,7,8].
Conclusion
GO:0014739 positive regulation of muscle hyperplasia is a biologically and clinically important process, particularly in vascular smooth muscle cells where excessive proliferation drives neointimal hyperplasia and cardiovascular disease [1,2,3,5,6,7,8]. Key regulators such as Nrf3-Trim5, PCSK9, PRMT5-KLF4, ferroptosis, NR1D1, MTMR7-p62/mTORC1 and SNHG18 provide mechanistic insights and therapeutic targets [1,2,3,5,6,7,8]. CRISPR-based models and EDITGENE services enable rigorous causal testing of these regulators.
References
- 1. Chen Q et al.. 2025. Novel roles of Nrf3-Trim5 axis in vascular smooth muscle cell dysfunctions and neointimal hyperplasia.. Cardiovasc Res 121(8):1282-1298 PMID: 40377016
- 2. Zhang Q et al.. 2025. PCSK9 promotes vascular neointimal hyperplasia through non-lipid regulation of vascular smooth muscle cell proliferation, migration, and autophagy.. Biochem Biophys Res Commun 742:151081 PMID: 39632291
- 3. Liu H et al.. 2023. Protein arginine methyltransferase 5-mediated arginine methylation stabilizes Kruppel-like factor 4 to accelerate neointimal formation.. Cardiovasc Res 119(11):2142-2156 PMID: 37201513
- 4. Xiao W et al.. 2016. Expression of MIF and c-erbB-2 in endometrial cancer.. Mol Med Rep 13(5):3828-34 PMID: 26985869
- 5. Zhang S et al.. 2022. Induction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice.. Mol Med 28(1):121 PMID: 36192693
- 6. Wang M et al.. 2023. Role of Nuclear Receptor Subfamily 1 Group D Member 1 in the Proliferation, Migration of Vascular Smooth Muscle Cell, and Vascular Intimal Hyperplasia.. J Cardiovasc Pharmacol 82(3):221-228 PMID: 37381169
- 7. Sun X et al.. 2024. MTMR7 suppresses the phenotypic switching of vascular smooth muscle cell and vascular intimal hyperplasia after injury via regulating p62/mTORC1-mediated glucose metabolism.. Atherosclerosis 390:117470 PMID: 38342025
- 8. Niu K et al.. 2024. Small nucleolar RNA host gene 18 controls vascular smooth muscle cell contractile phenotype and neointimal hyperplasia.. Cardiovasc Res 120(7):796-810 PMID: 38498586
